A conventional Cascade Impactor is a device used to determine the aerodynamic particle size distribution and mass concentration levels of solid particulates and liquid aerosols, from aerosolized dry powder and aerosolized liquid drug samples injected into the Cascade Impactor. Cascade Impactors are also used by the environment control and monitoring industry to determine particulate distributions from air samples. A variety of cascade impactors are commercially available. One reason for using Cascade Impactors in a testing environment is that air flowing inside the Cascade Impactors simulates air flowing into a human lung.
When delivering drugs through the respiratory tract to the lungs, whether in the form of micro ionized powders, or in the form of micron sized droplets of aerosolized mist from a solution, it is important to know the particle size distribution of the drug. Only drug particles of sizes generally less then 5 microns in diameter can penetrate deep into the lungs, and into the bronchi. Bigger particle sizes get ingested, and excreted out of the human body. The deep lung provides an enormous amount of surface area for the active drug substance to get absorbed in the blood steam, and thus permits the efficacious use of lower doses of drugs to get the same or better physiological response than drug delivery through the oral drug delivery route. Measurement of particle size distribution from injection of the drug into the Cascade Impactors is called a Dose Determination. The Dose Determination data from the Cascade Impactors is an integral part of a submission to the FDA as part of the NDA. Thousands of Dose Determinations need to be done, in order to meet the FDA's submission criteria for a new inhalation drug. Following the drug approval, thousands of Cascade Impactors tests are still needed to be performed over the lifetime of the inhalation drug, as an on-going quality control measure to continually prove to the FDA that the performance of the inhalation drug continues to meet the approval criteria of the drug.
Thus, in order to judge how efficacious the inhalation drug is when using inhalation devices, it becomes vitally important to generate the particle size distribution of doses of drugs delivered, and to fine tune the formulation of the inhalation drug.
Of the variety of Cascade Impactors commercially available, the conventional Andersen Cascade Impactor is the most popular. However, obtaining a Dose Determination from the Andersen Cascade Impactor it is very labor intensive, and therefore, an expensive process. Each Dose Determination from a contract lab can cost upwards of $1000. Typical throughput from each analyst operating an impactor to obtain a dose determination is two Dose Determinations per day. In addition, there are many parts that need to be carefully disassembled, and washed during use of a conventional cascade impactor to obtain a Dose Determination. Samples must be manually and very carefully collected from some of the impactor parts, and those parts must then be manually assembled again in preparation of the next Dose Determination. Therefore, manually determining a Dose Determination from the Andersen Cascade Impactor is very error prone and time consuming.
Conventional Andersen Cascade Impactors on the market today are fabricated using either Aluminum or Stainless Steel. A conventional Andersen Cascade Impactor is made up of a variable number of classification or impactor stages consisting of a series of jets and Impaction Plates. The number of Impactor Stages and Impaction Plates used to make up a column of the Andersen Cascade Impactor are variable, and depend on the drug and the particle size ranges that are to be measured. The Impaction Stages are stacked on top of each other, with succeeding Impaction Stages having smaller orifice diameters. Below each Impactor Stage is an Impaction Plate. During operation, as the drug suspended in an aerosol stream is delivered into the throat of the impactor and into the set of impaction stages, at each Impaction Stage, the aerosol stream passes through the jets or orifices and impacts upon the Impaction Plate.
Each Impactor Stage contains a multitude of orifices of the same diameter for that stage. Particles in the aerosol stream with significant inertia will settle upon the Impaction Plate for a given stage, while smaller particles pass as aerosols on to the next jet Impactor Stage. By designing consecutive Impactor Stages with higher aerosol jet velocities, smaller diameter particles are collected at each subsequent Impactor Stage (e.g. upon the impactor plate for that stage) giving the cascade affect of separation. The bottommost or lowest Impactor Stage contains a filter, to collect any drug that has not been collected on the Impaction Plates or the Impactor Stages. Typically the filter utilized is made of fiber media, or a very fine stainless steel mesh.
Sandwiched between succeeding stages is an O-Ring, so that all of the airflow is through the Impactor Stages, and none of the airflow leaks out of a seal formed between each impactor stage. Preventing airflow from leaking out of the Impactor is very important for obtaining reproducible experimental results. The Impactor Stages in a conventional impactor are tightly held by spring-loaded clamps, spaced 120 degrees apart around the circumference of the impactor, to ensure uniform closing pressure, and thus keeping the Impactor Stages tightly sealed. At the top of the stage assembly is a Pre-Separator Stage that simulates the back of the throat. The Pre-Separator Stage is where the bulk of the larger particle sizes are collected. Above the Pre-Separator is a Glass-Entry Throat. The inhaler is fitted into the Glass Entry Throat using an adapter.
The particle size range collected at each of the Impactor Stages depends on the jet orifice velocity of the specific Impactor Stage, the distance between the orifices and the collection surface, and the collection characteristics of the preceding Impactor Stage.
The combination of a constant flow rate, and successively smaller diameter orifices increase the velocity of sample air as it cascades through the Andersen Cascade Impactor, resulting in the impaction of progressively smaller particles in the succeeding Impactor Stages.
To operate the conventional Andersen Cascade Impactor, vacuum is applied to the bottommost Impactor Stage containing the filter, and a constant airflow is established through the Andersen Cascade Impactor. The inhaler is attached to the Glass Entry Throat on top of the Pre-Separator, and the drug is “inhaled” by the Impactor by dispensing one dose of the drug within the aerosol stream emitted from the inhaler into the throat of the impactor via the mouthpiece adapter. As the drug particles of differing particle size within the aerosol stream pass through the impactor, the particles get deposited onto different Impaction Plates, with the bigger particles on the top and smaller particles on the bottom Impaction Plates. After dispensing a single dose of the drug into the impactor, the Impaction Plates and the Impactor Stages are then manually disassembled by hand and each one of them carefully washed with solvent. Samples are collected in duplicate from each collection plate surface in the Andersen Cascade Impactor, and an analyst in the testing lab manually applies an HPLC technique to determine the drug content or collection amount of the surface for a given stage. The inhaler is weighed before and after drug injection into the Automated Andersen Cascade Impactor. Assuming mass balance, the particle size is deduced from the layer it was collected and the particle size distribution for the dose is drawn up.
Particle sizes less then 3-5 microns are the particles that travel deep into the lungs, permitting ready absorption of the drug into the blood, and thus are most efficacious. For this reason the US FDA and other regulatory agencies throughout the world require extensive particle size distribution data from the drug companies. At about two Dose Determinations per day using a conventional cascade impactor that operates by performing the test manually, it can take years to generate the data and get regulatory approval from the FDA.